The prevalence of chronic kidney disease (CKD) is high in patients with atrial fibrillation (AF). Left atrial appendage closure (LAAC) has been recognized as an efficient alternative to oral anticoagulation for the prevention of thromboembolic events in patients with non-valvular AF (NVAF); however, the long-term safety and efficacy of LAAC in patients with CKD remain unclear. This study was designed to provide data regarding the safety and efficacy of LAAC in NVAF patients with CKD. A real-world analysis of the safety and efficacy of LAAC was performed on a cohort of 300 NVAF patients with or without CKD who underwent LAAC using the Watchman (WM) device at our center. The patients with CKD (n = 151) were significantly older (77.0 ± 7.2 vs. 73.2 ± 7.8 years, respectively, P < 0.0001) and had a higher CHA2DS2-VASc score (4.3 ± 1.5 vs. 3.4 ± 1.4, respectively, P < 0.0001) and HAS-BLED score (4.0 ± 1.0 vs. 3.0 ± 1.0, respectively, P < 0.0001) than the patients without CKD (n = 149). However, there were no differences between groups with respect to the device implant success rate (98.7 vs. 97.3%, respectively, P = 0.446) or severe periprocedural complications within 7 days. The patients were followed up for 637 ± 398 days, and all patients received repeat transesophageal echocardiography (TEE). Thirteen (4.3%) device-related thrombi, 3 (1.0%) ischemic strokes, and 19 (6.3%) non-procedural major bleeding cases were documented, and there were no differences in these complications between groups. The observed rate of all thromboembolic events by Kaplan-Meier analysis decreased by 68.8% (CKD) and 48.6% (non-CKD); moreover, the observed annual rate of bleeding was reduced by 57.5% (CKD) and 11.4% (non-CKD). Our results indicate that LAAC with the WM device is safe and effective in preventing stroke in NVAF patients with and without CKD.